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WO2025180350A1 - Forme cristalline d'un sel composé, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un sel composé, son procédé de préparation et son utilisation

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Publication number
WO2025180350A1
WO2025180350A1 PCT/CN2025/078953 CN2025078953W WO2025180350A1 WO 2025180350 A1 WO2025180350 A1 WO 2025180350A1 CN 2025078953 W CN2025078953 W CN 2025078953W WO 2025180350 A1 WO2025180350 A1 WO 2025180350A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
ray powder
powder diffraction
diffraction pattern
Prior art date
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PCT/CN2025/078953
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English (en)
Chinese (zh)
Inventor
周岩锋
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Shanghai Apeiron Therapeutics Co Ltd
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Shanghai Apeiron Therapeutics Co Ltd
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Publication of WO2025180350A1 publication Critical patent/WO2025180350A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to the field of crystal chemistry, and specifically to pharmaceutically acceptable salts of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide and their crystalline forms.
  • a crystal is a solid in which compound molecules are arranged in a three-dimensional, orderly manner in a microstructure to form a crystal lattice.
  • Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms.
  • a compound may exist in one or more crystal forms, but its existence and properties cannot be specifically predicted.
  • the changes in properties caused by different crystal forms can also improve the final formulation form. For example, such changes can increase solubility and thus improve bioavailability, or improve the stability of the active ingredient, or more surprisingly, increase solubility while achieving good stability and lower hygroscopicity.
  • it is necessary to further study and improve its different crystal forms.
  • the technical problem to be solved by the present disclosure is to overcome the defect of compound I lacking a pharmaceutically acceptable salt form and crystal form and to improve its physicochemical properties, thereby providing a pharmaceutically acceptable salt of the compound represented by formula (I), which may be a hydrate, anhydrous form or a crystal of a solvate.
  • the present disclosure provides a pharmaceutically acceptable salt formed by Compound I and a pharmaceutically acceptable acid.
  • the pharmaceutically acceptable acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, oxalic acid, citric acid, tartaric acid, and the like.
  • the pharmaceutically acceptable salt of Compound I provided by the present disclosure has a molar ratio of the pharmaceutically acceptable acid to Compound I of preferably 1:2-2:1, more preferably 1:1 or 2:1.
  • the present disclosure provides pharmaceutically acceptable salts of Compound I that are physically and chemically stable under a range of storage conditions and amenable to additional processing.
  • the present disclosure provides a pharmaceutically acceptable salt of Compound I, preferably a p-toluenesulfonate, a maleate, a benzenesulfonate, a phosphate, an oxalate, a dibenzenesulfonate or a dihydrochloride salt.
  • the present disclosure provides pharmaceutically acceptable salts of Compound I, preferably the pharmaceutically acceptable salts are crystalline solids.
  • the present disclosure provides a pharmaceutically acceptable salt of Compound I, preferably the pharmaceutically acceptable salt is an anhydrate.
  • the present disclosure provides pharmaceutically acceptable salts of Compound I, including p-toluenesulfonate, maleate, benzenesulfonate, phosphate, oxalate, dibenzenesulfonate or dihydrochloride, which are preferably crystalline solids.
  • the p-toluenesulfonate and maleate salts provided by the present disclosure are preferably crystalline solids, more preferably anhydrous.
  • the present disclosure provides a maleate salt of Compound 1.
  • maleate salt crystalline form A a crystalline form of a maleate salt of Compound I (hereinafter referred to as "maleate salt crystalline form A").
  • the maleate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 3 using Cu-k ⁇ radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of the maleate salt form A is substantially as shown in Figure 4.
  • the results show that when the maleate salt form A is heated to 120°C, it has only a mass loss of 0.20%, and almost no mass loss; an endothermic peak begins to appear around 233.9°C.
  • the maleate salt Form A is an anhydrate.
  • the X-ray powder diffraction pattern of the maleate salt crystalline form A is 5.31° ⁇ 0.2°, 10.66° ⁇ 0.2°, 11.18° ⁇ 0.2°, 13.37° ⁇ 0.2°, 14.63° ⁇ 0.2°, 15.15° ⁇ 0.2°, 17.30° ⁇ 0.2°, 18.87° ⁇ 0.2°, 20.40° ⁇ 0.2°, 21.42° ⁇ 0.2°, 23.
  • the X-ray powder diffraction pattern of the maleate salt form A has a characteristic peak at a 2 ⁇ value of 5.31 ⁇ 0.2°, and arbitrarily has two characteristic peaks at 2 ⁇ values of 17.30 ⁇ 0.2°, 18.87 ⁇ 0.2°, 21.42 ⁇ 0.2°, 26.84 ⁇ 0.2°, 27.63 ⁇ 0.2°, and 30.56 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate salt form A has characteristic peaks at 2 ⁇ values of 5.31 ⁇ 0.2° and 18.87 ⁇ 0.2°, and arbitrarily has one characteristic peak at 2 ⁇ values of 17.30 ⁇ 0.2°, 21.42 ⁇ 0.2°, 26.84 ⁇ 0.2°, 27.63 ⁇ 0.2°, and 30.56 ⁇ 0.2°.
  • the maleate salt crystalline form A has an X-ray powder diffraction pattern with characteristic peaks at 2 ⁇ values of 5.31 ⁇ 0.2°, 17.30 ⁇ 0.2°, 18.87 ⁇ 0.2°, 21.42 ⁇ 0.2° and 27.63 ⁇ 0.2°.
  • the single crystal data of maleate salt form A are shown in Table 1. Table 1
  • the present disclosure provides the hydrochloride salt of Compound 1.
  • dihydrochloride salt crystalline form D a crystalline form of the dihydrochloride salt of Compound I (hereinafter referred to as "dihydrochloride salt crystalline form D").
  • the X-ray powder diffraction pattern of the dihydrochloride salt Form D is substantially as shown in FIG. 7 using Cu-k ⁇ radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of the dihydrochloride salt form D is substantially as shown in Figure 8. The results show that the dihydrochloride salt form D begins to lose mass at about 30°C, with multiple endothermic and exothermic signals.
  • the X-ray powder diffraction pattern of the dihydrochloride salt form D has characteristic peaks at any one, or two, or three, or four, or five, or six of the diffraction angle 2 ⁇ values of 9.33° ⁇ 0.2°, 14.05° ⁇ 0.2°, 17.81° ⁇ 0.2°, 18.86° ⁇ 0.2°, 23.89° ⁇ 0.2°, and 27.66° ⁇ 0.2°.
  • the present disclosure provides a hydrobromide salt of Compound 1.
  • hydrobromide salt crystalline form A a crystalline form of the hydrobromide salt of Compound 1 (hereinafter referred to as "hydrobromide salt crystalline form A").
  • the hydrobromide salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-k ⁇ radiation.
  • the X-ray powder diffraction pattern of the hydrobromide salt form A has characteristic peaks at any one of the diffraction angles 2 ⁇ values of 3.54° ⁇ 0.2°, 7.23° ⁇ 0.2°, 9.88° ⁇ 0.2°, 10.79° ⁇ 0.2°, 19.42° ⁇ 0.2°, 20.17° ⁇ 0.2°, 21.34° ⁇ 0.2°, 25.05° ⁇ 0.2°, and 32.58° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9.
  • dihydrobromide salt crystalline form A a crystalline form of the dihydrobromide salt of Compound I (hereinafter referred to as "dihydrobromide salt crystalline form A").
  • the X-ray powder diffraction pattern of the dihydrobromide salt Form A using Cu-ka radiation is substantially as shown in FIG. 10 .
  • the X-ray powder diffraction pattern of the dihydrobromide salt form A has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven of the diffraction angle 2 ⁇ values of 4.15° ⁇ 0.2°, 7.84° ⁇ 0.2°, 8.27° ⁇ 0.2°, 12.43° ⁇ 0.2°, 15.64° ⁇ 0.2°, 16.44° ⁇ 0.2°, and 16.89° ⁇ 0.2°.
  • the present disclosure provides a phosphate salt of Compound 1.
  • phosphate salt crystalline form A a crystalline form of the phosphate salt of Compound I (hereinafter referred to as "phosphate salt crystalline form A").
  • the X-ray powder diffraction pattern of the phosphate salt Form A using Cu-k ⁇ radiation is substantially as shown in FIG. 11 .
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of the phosphate crystal form A is substantially as shown in Figure 12. The results show that the phosphate crystal form A has only a 2.83% mass loss when heated to 120°C, and the first endothermic peak begins to appear around 67.7°C.
  • the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction angles 2 ⁇ of 6.26° ⁇ 0.2°, 11.66° ⁇ 0.2°, 12.54° ⁇ 0.2°, 13.62° ⁇ 0.2°, 15.95° ⁇ 0.2°, 18.54° ⁇ 0.2°, 18.83° ⁇ 0.2°, 20.69° ⁇ 0.2°, 21. There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14 of 24° ⁇ 0.2°, 21.65° ⁇ 0.2°, 22.32° ⁇ 0.2°, 23.42° ⁇ 0.2°, 24.86° ⁇ 0.2°, and 27.63° ⁇ 0.2°.
  • the present disclosure provides a besylate salt of Compound 1.
  • benzenesulfonate salt crystalline form A a crystalline form of a benzenesulfonate salt of Compound I (hereinafter referred to as "benzenesulfonate salt crystalline form A").
  • the besylate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 13 using Cu-ka radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of benzenesulfonate salt Form A is substantially as shown in Figure 14. The results show that benzenesulfonate salt Form A has only about 0.63% mass loss when heated to 120°C, and the first endothermic peak begins to appear around 218.7°C.
  • the besylate salt Form A is an anhydrate.
  • the X-ray powder diffraction pattern of the benzenesulfonate salt form A has characteristic peaks at any one of the diffraction angles 2 ⁇ values of 5.48° ⁇ 0.2°, 7.46° ⁇ 0.2°, 10.58° ⁇ 0.2°, 14.93° ⁇ 0.2°, 16.09° ⁇ 0.2°, 17.66° ⁇ 0.2°, 21.61° ⁇ 0.2°, and 30.75° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8.
  • the present disclosure provides a dibenzenesulfonate salt of Compound 1.
  • dibenzenesulfonate salt crystalline form A a crystalline form of a dibenzenesulfonate salt of Compound I (hereinafter referred to as "dibenzenesulfonate salt crystalline form A").
  • the dibenzenesulfonate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 15 using Cu-ka radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of dibenzenesulfonate salt Form A is substantially as shown in Figure 16. The results show that dibenzenesulfonate salt Form A has only about 1.15% mass loss when heated to 120°C, and an endothermic peak begins to appear around 180.2°C.
  • the dibenzenesulfonate salt Form A is an anhydrate.
  • the X-ray powder diffraction pattern of the dibenzenesulfonate salt form A has characteristic peaks at any one of the diffraction angles 2 ⁇ values of 4.66° ⁇ 0.2°, 5.73° ⁇ 0.2°, 9.23° ⁇ 0.2°, 16.44° ⁇ 0.2°, 17.27° ⁇ 0.2°, 19.93° ⁇ 0.2°, 20.64° ⁇ 0.2°, and 21.77° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8.
  • the present disclosure provides a p-toluenesulfonic acid salt of Compound 1.
  • p-toluenesulfonate salt crystalline form A a crystalline form of a p-toluenesulfonate salt of Compound I (hereinafter referred to as "p-toluenesulfonate salt crystalline form A").
  • the p-toluenesulfonate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 17 using Cu-ka radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of the p-toluenesulfonate crystalline form A is substantially as shown in Figure 18. The results show that the p-toluenesulfonate crystalline form A has almost no mass loss when heated to 120°C, and an endothermic peak begins to appear around 259.5°C.
  • the p-toluenesulfonate salt Form A is an anhydrate.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A has characteristic peaks at any one of the diffraction angles 2 ⁇ values of 5.42° ⁇ 0.2°, 10.74° ⁇ 0.2°, 14.52° ⁇ 0.2°, 15.18° ⁇ 0.2°, 17.15° ⁇ 0.2°, 17.65° ⁇ 0.2°, 20.12° ⁇ 0.2°, 20.65° ⁇ 0.2°, 21.47° ⁇ 0.2°, and 30.29° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.
  • the p-toluenesulfonate crystalline form A has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2 ⁇ of 5.42 ⁇ 0.2°, 10.74 ⁇ 0.2°, and 21.47 ⁇ 0.2°.
  • the present disclosure provides an oxalate salt of Compound 1.
  • oxalate salt crystalline form A a crystalline form of the oxalate salt of Compound I (hereinafter referred to as "oxalate salt crystalline form A").
  • the X-ray powder diffraction pattern of the oxalate salt Form A is substantially as shown in FIG. 20 using Cu-k ⁇ radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of the oxalate salt form A is substantially as shown in Figure 21.
  • the results show that the oxalate salt form A loses about 2.24% of its mass when heated to 120°C, and the first endothermic peak begins to appear around 35.8°C.
  • the X-ray powder diffraction pattern of the oxalate salt form A has characteristic peaks at any one of the diffraction angles 2 ⁇ of 5.20° ⁇ 0.2°, 7.85 ⁇ 0.2°, 10.46° ⁇ 0.2°, 13.11° ⁇ 0.2°, 15.52° ⁇ 0.2°, 16.51° ⁇ 0.2°, 17.46° ⁇ 0.2°, 18.29° ⁇ 0.2°, 19.56° ⁇ 0.2°, 20.98° ⁇ 0.2°, 25.95° ⁇ 0.2°, 27.11° ⁇ 0.2°, and 28.46° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically acceptable salt of Compound I of the present disclosure, and a pharmaceutically acceptable excipient.
  • the present disclosure provides use of a pharmaceutically acceptable salt of Compound I in the preparation of a pharmaceutical preparation for treating diseases associated with PRMT5 inhibitors.
  • the inventors further studied the reaction products of Compound I with acids such as maleic acid, p-toluenesulfonic acid, phosphoric acid, and oxalic acid. The studies revealed that the salts formed with the aforementioned acid ligands and Compound I exhibited good stability.
  • XRPD patterns were obtained using a Bruker D8 Advance diffractometer. Before the experiment, the voltage was set to 40 kV and the current was set to 40 mA. The sample was loaded onto a zero-background sample holder and scanned over an angle range of 2° to 40°. The scan step was set to 0.01°, and the wavelength of the X-ray used in the measurement was
  • the diffraction data were integrated and reduced using the SAINT program, and then empirically corrected for absorption using the SADABS program.
  • the single crystal structure was solved directly using SHELXT2014 and refined using the least squares method. Hydrogen atoms were refined using isotropic calculations. Hydrogen atoms on C-H were obtained by computational hydrogenation and refined using the riding model.
  • the Flack constant was 0.05 (12), and C8 was an S configuration.
  • DSC Differential scanning calorimetry experiments were performed using a Mettler-Toledo DSC3 differential scanning calorimeter (DSC). Prior to the experiment, the heating rate and melting enthalpy were calibrated using indium as a reference material. The sample was placed in a standard 40 ⁇ L aluminum crucible and then covered with a perforated lid. The weight of the sample was accurately recorded. The sample pan containing the sample was placed in the sample cavity. At the reference position, a standard 40 ⁇ L aluminum crucible was placed, which was configured in the same way as the sample pan except that it did not contain the sample. DSC measurements were performed by heating the sample from 30°C to 300°C at a heating rate of 10°C/min. Nitrogen was purged during the experiment at a flow rate of 50 mL/min.
  • TGA data were collected using a Mettler-Toledo TGA 2. Prior to sample analysis, the TGA 2 was calibrated with nickel. Samples were placed in an open aluminum pan, automatically weighed, and then placed in the TGA furnace. The furnace was heated from 31°C to 300°C at a heating rate of 10°C/min, with a nitrogen flow rate of 20 mL/min.
  • Moisture adsorption and desorption data were obtained using a dynamic vapor sorption instrument (Model TA Discovery SA). The sample was equilibrated at 25°C/0% RH for 300 minutes. Subsequently, the humidity level was controlled and maintained using nitrogen over a range of 0% to 95% RH in 5% RH steps. A mass change rate of less than 0.02%/min over 10 minutes was considered equilibrium during testing, with a maximum equilibration time of 120 minutes.
  • the data of the samples were collected using a Bruker 400 MHz nuclear magnetic resonance spectrometer with DMSO- d6 as the solvent.
  • the preparation method of the simulated gastrointestinal fluid involved in the present disclosure is:
  • SGF Weigh 2.02 g of sodium chloride into a 1000 mL beaker and dissolve the sodium chloride in 950 mL of purified water. Next, adjust the pH to 1.2 with 12 N hydrochloric acid. Transfer the solution to a 1000 mL volumetric flask and bring the volume to 1000 mL with purified water.
  • FeSSIF Weigh 4.04 g sodium hydroxide, 8.65 g acetic acid, and 11.87 g sodium chloride into a 1000 mL volumetric flask and dissolve in 950 mL of purified water. Titrate the resulting solution to pH 5.0 with 1 M sodium hydroxide or 1 M aqueous hydrochloric acid, then bring the volume to 1000 mL with purified water. Finally, weigh 11.20 g SIF powder and add it to 1000 mL of the pH 5.0 solution. Stir magnetically until clear.
  • FaSSIF Weigh 0.42 g sodium hydroxide, 3.44 g anhydrous sodium dihydrogen phosphate, and 6.19 g sodium chloride into a 1000 mL volumetric flask and dissolve in 950 mL of purified water. Titrate the resulting solution to pH 6.5 with 1 M sodium hydroxide or 1 M aqueous hydrochloric acid, then bring the volume to 1000 mL with purified water. Finally, weigh 2.240 g SIF powder and add it to 1000 mL of the pH 6.5 solution. Stir magnetically until dissolved.
  • centrifugation is performed by conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a speed of 10,000 rpm until all solids sink to the bottom of the centrifuge tube.
  • the drying is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying.
  • the drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C.
  • the drying time can be 2 to 48 hours, or, alternatively, drying is performed in a fume hood, forced air oven, or vacuum oven.
  • the “stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.
  • room temperature is not a specific temperature value, but refers to the temperature range of 10-30°C.
  • anhydrous substance refers to a solid substance that does not contain crystal water or crystallization solvent.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Ka radiation, the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” may be characterized by X-ray powder diffraction.
  • the XRPD diffraction data of a crystal has fingerprint characteristics.
  • different crystal forms are identified based on XRPD diffraction data. Those skilled in the art will select several representative peaks in the XRPD pattern as characteristic peaks to characterize the crystal.
  • the peak position, peak intensity, and peak shape are comprehensively considered.
  • the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the peak intensity of the diffraction peak in the X-ray powder diffraction pattern may also change with changes in the experimental conditions.
  • the peak intensity of the diffraction peak in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal.
  • the diffraction peak intensity shown in the present disclosure is illustrative rather than for absolute comparison. Therefore, when identifying whether the crystal forms are the same, the matching of the peak positions within the above-mentioned error range is the first priority.
  • the X-ray powder diffraction pattern of the crystal form protected by the present disclosure does not have to be completely consistent with the X-ray powder diffraction patterns in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is identical or similar to the characteristic peaks in these patterns falls within the scope of the present disclosure.
  • peaks are marked in an X-ray powder diffraction pattern, it refers to any X-ray powder diffraction pattern that has an error within the range of ⁇ 0.2° from the peaks in these patterns.
  • Those skilled in the art can compare the X-ray powder diffraction patterns listed in the present disclosure with the X-ray powder diffraction patterns of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the pharmaceutically acceptable salts of Compound 1 and crystalline forms thereof disclosed herein are pure and substantially free of any other crystalline forms.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more particularly less than 5% (by weight) of other crystalline forms, and even more particularly less than 1% (by weight) of other crystalline forms.
  • the XRPD pattern of maleate salt Form A is shown in FIG3 , and the XRPD data are shown in Table 7.
  • the TGA and DSC curves of maleate salt form A are shown in FIG4 .
  • the results show that when heated from 31° C. to 120° C., its weight loss is 0.20%.
  • the DSC spectrum shows an endothermic peak with an onset temperature of 233.89° C., which is a melting peak.
  • the TGA and DSC curves of dihydrochloride Form D are shown in FIG8 .
  • the results show that dihydrochloride Form D begins to lose mass at about 30° C., with multiple endothermic and exothermic signals.
  • High hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, directly impacting their physicochemical stability. Furthermore, high hygroscopicity can reduce API flowability, impacting API processing. Furthermore, highly hygroscopic drugs require low humidity during production and storage, placing higher demands on production and incurring significant costs.
  • the maleate salt Form A was subjected to a DVS test. The results are shown in Figure 24. From 0% to 80% relative humidity, the maleate salt Form A experienced a moisture absorption weight gain of approximately 0.25%, demonstrating very low hygroscopicity. XRPD characterization of the sample after DVS testing, as shown in Figure 25, demonstrates that the crystal form remained unchanged after the DVS test, demonstrating that the maleate salt Form A exhibits good humidity stability.
  • Maleate Form A exhibits good physicochemical stability when stored at 25°C/60% RH, 40°C/75% RH, and 60°C for four weeks, helping to prevent drug quality from being affected by crystal transformation or purity loss during storage.
  • Airflow Milling Maleate Form A powder was airflow milled using the process parameters listed in Table 3. The airflow milled powder was subsequently subjected to XRPD and PLM analysis, with the results shown in Figures 27 and 28, respectively. The results indicate that after airflow milling, the crystalline form of the maleate Form A remained unchanged, while the crystal size was significantly reduced.
  • Pressurization method The maleate salt Form A was weighed and transferred into a 5 mm diameter die. The upper piston was then manually lowered into the die orifice until a pressure of 40 MPa was reached, which was maintained for 1 minute. The sample was then removed and manually pulverized into a powder. Finally, the resulting powder was subjected to XRPD analysis. The results showed that the maleate salt Form A did not change in crystalline form after pressurization.
  • 200 mg of the mixed powder was transferred to the die of a rotary tablet press with a diameter of 8 mm.
  • One tablet was compressed at a pressure of 4.2 kN and the other tablet was compressed at a pressure of 9.2 kN.
  • the remaining 800 ⁇ L of suspension in the bottle was centrifuged at 8000 rpm for 10 minutes.
  • the pH of the resulting supernatant was measured, and the precipitated solid was dried under vacuum at 40°C for approximately 16 hours.
  • the dried precipitated solid was then scanned using X-ray powder diffraction.
  • maleate salt form A had high solubility in both SGF and FeSSIF, and the crystal form did not change after 24 hours of solubility testing in SGF, FeSSIF and water, indicating that it had good physical stability in the above media.
  • Maleate salt form A has a higher solubility, which is beneficial to improving drug absorption in the human body and increasing bioavailability; in addition, higher solubility can reduce the dosage of the drug while ensuring the drug's efficacy, thereby reducing the drug's side effects and improving the drug's safety.
  • High hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, directly impacting their physicochemical stability. Furthermore, high hygroscopicity can reduce API flowability, impacting API processing. Furthermore, highly hygroscopic drugs require low humidity during production and storage, placing higher demands on production and incurring significant costs.
  • the remaining 800 ⁇ L of suspension in the bottle was centrifuged at 8000 rpm for 10 minutes.
  • the pH of the resulting supernatant was measured, and the precipitated solid was dried under vacuum at 40°C for approximately 16 hours.
  • the dried precipitated solid was then scanned using X-ray powder diffraction.
  • the p-toluenesulfonate crystalline form A has a higher solubility, which is beneficial to improving the absorption of the drug in the human body and improving the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • Form A of the p-toluenesulfonate salt exhibits good physicochemical stability when stored at 25°C/60% RH, 40°C/75% RH, and 60°C for four weeks, helping to prevent drug quality from being affected by crystal transformation or purity loss during storage.

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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une forme cristalline d'un sel de (S)-4-amino-N-méthyl-N-(6-(trifluorométhyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-formamide (ci-après appelé "composé I"), son procédé de préparation, une composition pharmaceutique contenant le sel de composé I, et une utilisation du sel de composé I dans la préparation d'un médicament inhibiteur de PRMT5.
PCT/CN2025/078953 2024-02-26 2025-02-25 Forme cristalline d'un sel composé, son procédé de préparation et son utilisation Pending WO2025180350A1 (fr)

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CN202410211544 2024-02-26

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WO2025180350A1 true WO2025180350A1 (fr) 2025-09-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009845A1 (fr) * 1997-08-25 1999-03-04 Bristol-Myers Squibb Company Inhibiteurs a base d'imidazoquinoxalines de la proteine tyrosine kinase
WO2004085439A1 (fr) * 2003-03-27 2004-10-07 Pfizer Products Inc. 4-amino[1,2,4]triazolo[4,3-a]quinoxalines substitutees
WO2024037459A1 (fr) * 2022-08-18 2024-02-22 南京明德新药研发有限公司 Dérivés hétérocycliques contenant des amides et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009845A1 (fr) * 1997-08-25 1999-03-04 Bristol-Myers Squibb Company Inhibiteurs a base d'imidazoquinoxalines de la proteine tyrosine kinase
WO2004085439A1 (fr) * 2003-03-27 2004-10-07 Pfizer Products Inc. 4-amino[1,2,4]triazolo[4,3-a]quinoxalines substitutees
WO2024037459A1 (fr) * 2022-08-18 2024-02-22 南京明德新药研发有限公司 Dérivés hétérocycliques contenant des amides et leur utilisation

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